HIV Vaccine Approaches

DCharlotte Raymond/IAVIevising an effective vaccine to prevent HIV infection or curtail its progression remains one of the greatest scientific challenges. This is because the virus has developed multiple mechanisms to evade the body’s defenses. Very soon after it enters a human body, HIV weaves itself into the DNA of its target cells, creating a lasting reservoir of infection. It also targets the very cells that coordinate the immune response to viral infections. But, more than anything else, it is the extraordinary ability of the virus to mutate that makes it a formidable foe for the body’s immunologic weaponry. Fortunately, recent scientific discoveries, as well as the results from the RV144 trial that demonstrated for the first time that a vaccine can prevent HIV infection, have reinvigorated the field and generated considerable optimism about the prospects of an effective AIDS vaccine.

Vaccinologists are working simultaneously on two major approaches to designing preventive HIV vaccines: engaging the immune system to block infection, and training the body to recognize and destroy cells infected by HIV. IAVI believes that a vaccination strategy that engages both mechanisms of the immune response will provide the most robust protection from HIV.

Blocking Infection: The Antibody ResponseAll licensed viral vaccines are effective in preventing disease by stimulating the immune system to produce protective antibodies. But HIV’s extraordinary ability to mutate serves as a molecular disguise, allowing it to constantly evade antibodies from latching on and neutralizing the virus. Some relatively rare antibodies are, however, known to be able to neutralize a wide spectrum of HIV variants. Researchers suspect that a vaccine that elicits similar antibodies might be able to neutralize HIV before it has an opportunity to establish a lasting infection. The close study of broadly neutralizing antibodies could reveal how that might be accomplished.

Until 2009, researchers had only a handful of such antibodies to use as a reference to design vaccines capable of this feat. But in September 2009, researchers at and affiliated with IAVI reported the isolation of two exceptionally potent broadly neutralizing antibodies. Since then, dozens of such antibodies have been identified by these researchers and IAVI’s partners at the Vaccine Research Center (VRC) of the United States National Institutes of Health, as well as other researchers. The structural and biochemical analysis of these antibodies are yielding valuable clues for vaccine design.

Destroying Infected Cells: The Cell-Mediated ResponseThe other arm of the immune response involved in clearing viral infections is known as cell-mediated immunity (CMI), in which the body’s T cells (including the type targeted by HIV) work together to destroy cells in the body that have already been infected by HIV. Vaccinologists employ several strategies to design vaccine candidates that might teach the immune system how to target HIV-infected cells. Two of the major approaches are:

Introducing bits of HIV’s genetic code into naked loops of DNA that are taken up by human cells

Alternatively, inserting those genes into viruses—or vectors—that do not cause disease and have been engineered to be incapable of multiplying after they enter their target cells

In either case, the production of proteins encoded by these genetic vehicles teaches the immune system how to recognize an HIV-infected cell and destroy it. More recently, researchers at IAVI and elsewhere have sought to develop vectors that retain the ability to multiply safely after delivery in the hope that their persistence and replication will induce stronger, broader and more durable immune responses to the HIV proteins they bear.